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L’infection par le VIH-1 est caractérisée par une activation chronique du système immunitaire et par une réduction graduelle du nombre de lymphocytes TCD4+, qui contribuent à une détérioration lente du système immunitaire menant à la phase SIDA. Paradoxalement, ce sont majoritairement des lymphocytes T CD4+ non infectés qui sont détruits et la cause de ce phénomène reste encore inconnue. Certaines protéines virales, dont la protéine accessoire Vpr, sont soupçonnées de jouer un rôle dans ce processus. Synthétisée tardivement, Vpr est incorporée à l’intérieur des virions, en plus d’être relâchée sous forme soluble dans le milieu extracellulaire. La principale fonction biologique de Vpr est l’induction d’un arrêt de cycle en phase G2/M, via le recrutement du complexe d’ubiquitine E3 ligase CUL4A-DDB1VprBP et l’activation de la voie de dommage à l’ADN contrôlée par la kinase ATR. Une étude démontre que l’activation des voies de dommages à l’ADN conduit à l’expression de ligands du récepteur activateur NKG2D, exprimés par les cellules NK, déclenchant leurs fonctions cytolytiques. Chose intéressante, plusieurs études suggèrent que le VIH-1 régule positivement l’expression des ligands de NKG2D à la surface des lymphocytes T CD4+ infectés. Cependant, le facteur viral impliqué dans ce processus reste encore indéfini. Le but de cette thèse était d’évaluer le rôle de Vpr dans la modulation des fonctions cytolytiques des cellules NK et son implication potentielle dans la destruction des lymphocytes T CD4+. Nos travaux ont permis de démontrer que l’expression de Vpr, seule ou dans le contexte de l’infection, est suffisante afin d’augmenter spécifiquement l’expression du ligand de NKG2D, ULBP2, au niveau de lymphocytes T CD4+ primaires. Conséquemment, Vpr augmente ainsi la susceptibilité de ces cellules à une lyse par des cellules NK autologues. Nous démontrons que cette régulation positive d’ULBP2 repose sur la capacité de Vpr de recruter le complexe d’ubiquitine E3 ligase DDB1-CUL4AVprBP et l’activation de la voie de dommage à l’ADN ATR. Plus important encore, nous apportons des preuves que Vpr augmente également l’expression d’ULBP2 au niveau des cellules non infectées lors d’une infection de lymphocytes TCD4+ par le VIH-1. À cet effet, nous montrons que l’acheminement de Vpr au niveau de lymphocytes T CD4+ non infectés via des particules virales défectives est suffisant afin de réguler positivement ULBP2 et d’augmenter leur lyse par des cellules NK autologues. De plus, nous décrivons pour la première fois que Vpr, sous forme soluble, a la capacité d’induire des dommages à l’ADN et de réguler positivement ULBP2 suite à la transduction de différents types cellulaires, incluant des cellules T. Globalement, nos résultats démontrent que Vpr est un facteur viral clé impliqué dans la régulation positive des ligands de NKG2D induite par le VIH-1. Cette régulation positive d’ULBP2 pourrait alors contribuer à la destruction des lymphocytes T CD4+ infectés et non infectés via l’activation des fonctions cytolytiques des cellules NK. Une meilleure compréhension de la contribution de cette activité de Vpr dans la pathogenèse du VIH-1 a le potentiel de permettre le développement de nouvelles cibles ou stratégies thérapeutiques contre le VIH-1., Chronic immune activation and gradual depletion of CD4+ T cells are hallmarks of HIV-1 infection, which are thought to contribute to the progressive deterioration of the host’s immune response that ultimately leads to AIDS. Paradoxically, the majority of CD4+ T cells that are destroyed are uninfected and causes for this bystander effect of infection on CD4+ T cells remains unclear. Some HIV-1 proteins, including the accessory protein Vpr, are suspected to play a role in this process. Vpr, expressed late during HIV-1 infection, is shown to be incorporated within the budding virions as well as secreted as soluble protein in the extracellular medium from the infected cells. The main biological function of Vpr is the induction of a G2/M cell-cycle arrest through the recruitment of the E3 ubiquitin ligase complex DDB1-CUL4AVprBP and activation of the ATR-mediated DNA damage pathway. One study showed that activation of DNA damage pathways leads to the expression of specific ligands for the activating receptor NKG2D expressed on NK cells, thus triggering NK cell cytolytic function. Interestingly, several evidences suggest that HIV-1 upregulates expression of specific NKG2D ligands on infected CD4+ T cells. However, the viral factor involved in this process remains undefined. The aim of this thesis was to evaluate the role of Vpr in modulating NK cell cytolytic function and its potential involvement in CD4+ T cells depletion. Our work demonstrated that the expression of Vpr, alone or in the context of HIV-1 infection, is sufficient to specifically increase expression of the NKG2D ligand, ULBP2, on primary CD4+ T cells. Consequently, these CD4 T cells become more susceptible to autologuous NK cell-mediated lysis. Our studies have shown that this Vpr-mediated ULBP2 upregulation requires the recruitment of the E3 ubiquitin ligase complex DDB1-CUL4AVprBP and the activation of the ATR-mediated DNA damage pathway. More importantly, we provide evidence that Vpr augments ULBP2 expression on both infected and uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. In that context, we show that delivery of Vpr into uninfected cells via defective viral particles is sufficient to upregulate ULBP2 and increase their susceptibility to autologuous NK cell-mediated killing. In addition, we describe for the first time that soluble Vpr has the ability to induce DNA damages and upregulate ULBP2 upon transducing target cells, including T cells. Overall, our results show that Vpr is a key HIV-1 factor involved in the upregulation of NKG2D ligands induced by HIV-1. This upregulation of UBP2 might contribute to depletion of infected and uninfected CD4 + T cells through activation of NK cell cytolytic functions. A better understanding of the contribution of this new activity of Vpr in HIV-1 pathogenesis has the potential to enable the development of new therapeutic targets or therapeutic strategies against HIV-1.

This thesis explores, develops and implements modelling strategies for studying relationships between childhood growth and later health, focusing primarily on the relationship between the development of body mass index (BMI) in childhood and later obesity. Existing growth models are explored, though found to be inflexible and potentially inadequate. Alternative approaches using parametric and nonparametric modelling are investigated. A distinction between balanced and unbalanced data structure is made because of the ways in which missing data can be addressed. A dataset of each type is used for illustration: the Stockholm Weight Development Study (SWEDES) and the Uppsala Family Study (UFS). The focus in each application is obesity, with the first examining how the adiposity rebound (AR), and the second how the adiposity peak (AP) in infancy, relate to later adiposity. In each case a two-stage approach is used. Subject-specific cubic smoothing splines are used in SWEDES to model childhood BMI and estimate the AR for each subject. As childhood BMI data are balanced, missingness can be dealt with via mUltiple imputation. The relationship between the AR and late-adolescent adiposity is then explored via linear and logistic regression, with both the age and BMI at AR found to be strongly and independently associated with late-adolescent adiposity. In the UFS, where childhood BMI data are unbalanced, penalised regression splines are used within a mixed model framework to model childhood BMI and estimate the AP for each subject. The data correlations induced by the family structure of the observations are addressed by fitting multilevel models in the second stage. Both age and BMI at AP are found to be positively associated with later adiposity. The two nonparametric modelling approaches are found to be effective and flexible. Whilst the thesis concentrates on BMI development in childhood and later adiposity, the techniques employed, both in terms the modelling of growth and the relating of the derived features to the outcomes, are far more widely applicable.

Modern radio interferometer arrays are powerful tools for obtaining high resolution images of low frequency electromagnetic radiation signals in deep space. While single dish radio telescopes convert the electromagnetic radiation directly into an image of the sky (or sky intensity map), interferometers convert the interference patterns between dishes in the array into samples of the Fourier plane (UV-data or visibilities). A subsequent Fourier transform of the visibilities yields the image of the sky. Conversely, a sky intensity map comprising a collection of point sources can be subjected to an inverse Fourier transform to simulate the corresponding Point Source Visibilities (PSV). Such simulated visibilities are important for testing models of external factors that affect the accuracy of observed data, such as radio frequency interference and interaction with the ionosphere. MeqTrees is a widely used radio interferometry calibration and simulation software package that contains a Point Source Visibility module. Unfortunately, calculation of visibilities is computationally intensive: it requires application of the same Fourier equation to many point sources across multiple frequency bands and time slots. There is great potential for this module to be accelerated by the highly parallel Single-Instruction-Multiple-Data (SIMD) architectures in modern commodity Graphics Processing Units (GPU). With many traditional high performance computing techniques requiring high entry and maintenance costs, GPUs have proven to be a cost effective and high performance parallelisation tool for SIMD problems such as PSV simulations. This thesis presents a GPU/CUDA implementation of the Point Source Visibility calculation within the existing MeqTrees framework. For a large number of sources, this implementation achieves an 18x speed-up over the existing CPU module. With modications to the MeqTrees memory management system to reduce overheads by incorporating GPU memory operations, speed-ups of 25x are theoretically achievable. Ignoring all serial overheads, and considering only the parallelisable sections of code, speed-ups reach up to 120x.

El propósito de la presente investigación, es reconocer los elementos relevantes de la multiculturalidad, como variable indirecta en el proceso de obtener la licencia social para operar en el Perú (en adelante LS). Con este propósito, los aspectos relevantes en este trabajo se relacionan a: (i) establecer la forma en que los elementos de la multiculturalidad se relacionan con el diálogo y demás variables vinculadas directamente con el proceso de obtener la LS en el Perú, (ii) entender cuál es el rol e influencia de multiculturalidad y su relación con la confianza, legitimidad y legalidad en el proceso de obtener la LS, y la percepción que se tiene del rol del Estado y, (iii) proponer modelos conceptuales para convertir la multiculturalidad en un activo valioso para las industrias extractivas en un marco de valor compartido. Mediante el análisis de entrevistas a expertos sobre el tema y el estudio de diversos documentos y libros de autores peruanos y extranjeros, se evidenció la importancia de: (i) la multiculturalidad como factor relevante indirecto en el diálogo y el proceso de gestión de la LS para operar, en un entorno de buena fe y valor compartido, y (ii) la importancia de construir legitimidad y el marco de la legalidad, como facilitadores para la obtención de LS. Se concluyó que para obtener la licencia social en el Perú es necesario, en un entorno de buena fe, confianza, credibilidad, y pautas de valor compartido, reconocer la relevancia de la multiculturalidad y sus elementos relevantes en este proceso, no como un obstáculo, sino como una ventaja comparativa que deben identificar e incorporar las industrias extractivas en sus organizaciones de manera que las operaciones de estas industrias puedan ser no solo legales, sino también legítimas, alcanzando así una sólida licencia social para operar The purpose of this research is to recognize the relevant elements of multiculturalism, as indirect variable in the process of obtaining the social license to operate in Perú (LS). For this purpose the relevant aspects in this research is related to: (i) establish the manner in which the elements of multiculturalism are related to dialogue and other variables directly linked to the process of getting the LS in Peru, (ii ) understand the role and influence of multiculturalism and its relationship with trust, legitimacy and legality in the process of getting the LS, and the perception of the role of the state and (iii) propose conceptual models to convert multiculturalism in a valuable asset for the extractive industries within a framework of shared value. By analyzing interviews with experts on the theme and the study of various documents and books by Peruvian and foreign authors, its showed the importance of: (i) multiculturalism as an indirect and relevant factor in the dialogue and management process of the LS to operate, in an environment of good faith and shared value, and (ii) the importance of building legitimacy and the legal framework and institutional innovation, as facilitators to obtain social license. It was concluded that to obtain the social license in Peru it is necessary, in an environment of good faith and shared value, recognize the key importance of multiculturalism and its relevant elements in this process, not an obstacle, but as a comparative advantage that extractive industries should incorporate into their organizations. On this basis, we can build trust and credibility for extractive operations, which can be not only legal but also legitimate, thus achieving a solid and enduring social license to operate Tesis

Objectives: The aim of this pilot study was to investigate whether measurement of the bioelectrical impedance of the lower limb could be used to measure the swelling resulting from acute ankle fracture. Methods: The impedance of each ankle was measured in 14 patients with isolated acute ankle fracture. The degree of ankle swelling was also directly assessed by measurement of the ankle circumference and diameter and by the water displacement method. A control group of 17 healthy subjects with uninjured ankles was similarly assessed. Results: The impedance of the ankle was significantly reduced in patients with ankle fracture, and there was a strong inverse relationship between the degree of this reduction and the amount of swelling as directly measured. The relationship was stronger using the impedance method than the circumference and diameter methods. Conclusions: We conclude that bioelectrical impedance can be used to measure ankle swelling in the presence of injury and could potentially be used both to monitor swelling clinically and as a research tool in studies of swelling management. More research is required to further define the potential role for this technique.

This essay seeks to address some of the social concerns surrounding the practice of prenatal testing in a preliminary fashion, through a review of the existing literature and research on the topic. The focus is placed on a discussion of the claims that prenatal testing constitutes a new form of eugenics in that it is primarily concerned with the diagnosis and therapeutic abortion of fetuses that have disabling, but not imminently life-threatening conditions, and a theoretical contextualization of how prenatal testing represents a larger shift in contemporary governance of health from the state as biopolitician to the individual as biopolitician. The essay begins with a summary of prenatal testing practices and terminology, followed by a brief history of eugenics, human genetics and genetic counselling. Next, an assessment of prenatal testing and the operation of biopolitics is made followed by a discussion of how prenatal testing exposes the limits of Foucault’s concept of biopolitics. Nikolas Rose’s reconceptualization of biopolitics as riskpolitics, molecularpolitics and ethopolitics under the prevailing ideology of neo-liberalism is then used to frame the new operation of biopower. Finally, the arguments for and against the characterization of prenatal testing as a eugenic practice are examined followed by a discussion of the concerns that surround this practice. This essay concludes that a clear historical lineage can be traced between contemporary prenatal testing and previous eugenic movements and that prenatal testing could be constituted as eugenic in that it is leading to a significant reduction in the number of children born with certain disabling conditions. However, the terminology of eugenics draws attention away from the ultimate discussion of whether or not this technology is discriminatory and how might the implicit forms of discrimination be rectified. A number of specific and realistic recommendations for doing this are suggested.

This paper will give an overview of some recent developments in electroholography for applications in interactive 3D visualisation. Arguably the ultimate technology for this task, it is the only approach having the potential to deliver full depth cue, 3D images, having resolutions beyond that which can be perceived by the human eye. Despite significant advances by many researchers, the high pixel counts required by the computer generated hologram (CGH) patterns in these systems remain daunting - in practice, systems able to calculate and display reconfigurable CGH having pixel counts of more than one billion may be required for 300 mm width, 3D images. Advances described include novel Fourier mode variants of diffraction specific algorithms and parallel binarisation techniques for design of the CGH patterns; computer architectures for effective implementation of these algorithms for interactive CGH calculation; the latest developments in the Active Tiling spatial light modulator technology and novel replay optics arrangements including folded mirror geometries, viewer tracking alternatives and new horizontal parallax configurations. Throughout, the emphasis is optimisation towards implementation as an interactive electroholography system having practical utility. Some recent results from demonstrations of aspects of the technology will be shown. These include monochrome and colour, static and dynamic, horizontal parallax only (HPO) and full parallax, 3D images, generated from true CGH systems with up to 24 billion pixels.

Reconfigurable computer generated holography - sometimes known as electroholography - is the only technique capable of using computer held data to generate interactive, high quality, 3D images containing all the depth cues used by the human visual system. Practical applications of electroholography require computer generated hologram (CGH) patterns of between 10/sup 9/ to 10/sup 10/ pixels to be calculated and displayed at interactive rates. These pixel counts are necessary in order to generate images which are both big enough (upwards of 300 mm width) and possess a large enough field of view (FOV) to permit simultaneous, multiuser viewing. Advances in several key areas may now make such high performance electroholographic systems practical in the near future. We describe CGH design algorithms, computer architectures and CGH display engines, including the Active Tiling/spl trade/ system.

Giga-pixel scale displays or spatial light modulators are required in order to form directly viewable 3-D images of 0.5m in size using the principles of computer generated holography (CGH). This has been a key bottleneck preventing commercial development of electro-holography. Active Tiling is a modular spatial light modulator system developed by the authors to provide a route to replay images from giga-pixel scale CGHs. This paper will present the latest development of a multi-channel Active Tiling unit and results from this system for the first time. A holographic 3D display system using a 4 channel Active Tiling modulator with a new replay optics system has demonstrated directly viewable 3-D images and animations from 100 Mega-pixel CGH data. This provided viewing of both horizontal parallax only (HPO) and full parallax 3-D images up to 140mm in size. 25 Mega-pixels of CGH data is written by each channel onto a liquid crystal optically addressed spatial light modulator at high resolution. The modular design of Active Tiling permits CGH data to be written seamlessly across multiple channels which can be updated at rates up to 30 Hz. A Fourier Transform optical replay system was developed and integrated with the 4-channel Active Tiling system to form the CGH images.

Continuing advances in both computing and modulator techniques and technologies increase the likelihood of electro-holography displays becoming practical in the next five years or so. These displays aim to allow high quality, interactive, 3D images to be generated from compte held dat. Until now, large pixel counts have precluded any systems of practical utility. This paper will describe recent progress towards meeting the challenges of implementing such displays. Despite more than exponential increases in computer performance, interactive hologram calculation remains an issue. A significant part of the cost of any electro-holography product will be associated with the computational requirements. These are strongly influenced by the choice of computer generated hologram (CGH) type, the algorithm used to calculate the CGH and the computer architecture chosen for implementation. The leading optics will be discussed and some experimental results presented indicating performance, cost and image quality tradeoffs. Eventual choice will depend on the specifications of the required system. Another traditional bottleneck has been the optical modulator employed. As one of the leading candidates for practical implementation, the current and projected performance of the DERA Active Tiling system will be explored, and the latest experimental results presented. These will include the first published, full parallax, true CGH, 3D image replays from an Active Tiling channel.